Gastrointestinal inflammatory diseases or gastric acid-related diseases, including peptic ulcer, gastric and duodenal ulcer, gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and the like, are the most common gastrointestinal diseases that affect most people in the world, including Korea.
Antiulcer agents, which are classified as agents for treating such diseases, are divided into two categories: drugs that inhibit aggressive factors such as gastric acid or pepsin; and drugs that enhance defensive factors such as sucralfate or misoprostol. Among these a representative therapeutic agents, various drugs have been used in the past as agent to inhibit aggressive factors such as antacids, anticholinergic drugs, H2 receptor antagonists, proton pump inhibitors (PPIs) and the like. However, currently, proton pump inhibitor (PPI) drugs represented by Omeprazole, Lansoprazole, Pantoprazole, Raveprazole and the like are leading the market.
The proton pump is H+/K+-ATPase that releases H+ into parietal cells and absorbs K+ in the final stage of a gastric acid secretion response caused by binding of various acid secretion stimulators (histamine, acetylcholine, gastrin and the like) to their receptors present in parietal cells in vivo. Thus, proton pump inhibitors (PPIs) are drugs that inhibit gastric acid secretion by inhibiting the H+/K+-ATPase of parietal cells, which is the final stage of gastric acid secretion. These proton pump inhibitors (PPIs) are more effective and long-lasting in inhibiting gastric acid compared to prior drugs, and thus have been widely used for the past 20 years as therapeutic agents against peptic ulcer, gastric and duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD) and the like. In particular, gastroesophageal reflux disease (GERD) is a chronic recurrent disease whose patients recently have rapidly increased in number, and it is an inflammatory disease that causes esophageal (adenocarcinoma) through the Barrett's esophagus when progressing to a chronic stage. The treatment rate of this gastroesophageal reflux disease (GERD) has increased rapidly since launching of proton pump inhibitors (PPIs).
However, it was reported that, since existing proton pump inhibitors (PPIs) are converted to an active sulfenamide form by acid secretion, and then bind irreversibly to the cysteine residues of H+/K+-ATPase to thereby inhibit gastric acid secretion for a long period of time, they may cause adverse effects, including gastric bacterial growth, stimulation of proton pump expression, and tumor cell formation due to hypergastrinemia [Havu N, Digestion, 1986, 35 (Suppl 1), 42-55; Chang Seok Song, Dong II Park, Korean J Med., 2011, 81 (1), 6-10]. Furthermore, it was recently reported that, when these proton pump inhibitors (PPIs) are used over a long period of time, they inhibit calcium absorption ability and bone cell growth due to gastric acid inhibition, thereby increasing the risk of fractures of the hip joint, carpus and spine [Yang Y X, et al., JAMA, 2006, 296, 2947-53; Targownik L E, et al., CMAJ, 2008, 179 (4), 319-26; Gray S L, et al., Arch Intern Med. 2010, 170 (9), 765-71]. In addition, due to an increase in the elderly population, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased, and the development of various medical technologies has led to an increase in survival rate against various diseases, resulting in an increase in the number of patients with peptic ulcer and gastroesophageal reflux disease (GERD) induced by various causes. Furthermore, the number of patients refractory to proton pump inhibitors (PPIs) has also increased in spite of the very effective therapeutic ability of the proton pump inhibitors (PPIs).
Accordingly, among recent proton pump inhibitors (PPIs), there is an increasing interest and need for potassium competitive acid blocker (P-CAB, acid pump antagonist) drugs having a mechanism by which they bind reversibly to the K+ binding site of H+/K+-ATPase to inhibit acid secretion in a potassium-competitive manner. Particularly, it is expected that unlike the irreversible proton pump inhibitors (PPIs), the reversible potassium competitive acid blockers (P-CABs) will exhibit fast efficacy in view of their mechanism, will be easily taken before or after a meal, and will be very effective in nighttime symptoms, which is a problem of irreversible proton pump inhibitors.
The present disclosure also relates to reversible proton pump inhibitors (P-CABs), and typical examples of reversible proton pump inhibitors known in the art include pyrrole derivative TAK-438 [Takeda Pharmaceutical Co. Ltd.; WO2007/026916], pyrrolo[2,3-c]pyridine YH-4808 [Yuhan Corp.; WO2006/025716], 1H-benzo[d]imidazole derivative CJ-12420 [Pfizer Inc., Japan, Raqualia Pharma Inc.; WO2007/072146], and imidazo[1,2-α]pyridine derivative AZD0865 [AstraZeneca AB; WO99/55705 and WO99/55706].
Accordingly, the present inventors have studied to develop low-molecular-weight reversible proton pump inhibitors that can be effectively used for the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases, including peptic ulcer, gastric and duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and the like. As a result, the present inventors have prepared novel imidazo[1,2-α]pyridine derivatives during such studies and have found that these derivatives exhibit excellent proton pump inhibitory activity, thereby completing the present disclosure.